7-carboxy-flavone derivatives preparation method and therapeutic use

ABSTRACT

The invention concerns novel flavone and isoflavone derivatives of formulae (Ia) and (Ib) wherein: X represents a group of formula —COOR, or —PO(OR) 2 ; R represents a hydrogen atom or an alkaline or alkaline-earth metal, or a lower alkyl group; R 1  represents a hydroxy group, a lower alkoxy group or an acyloxy group; R 2  and R 3 , identical or different, represent a hydrogen or halogen atom, or a trifluoromethyl group, a trichloromethyl group, a hydroxy group, an alkoxy group or an acyloxy group comprising 1 to 5 carbon atoms, or R 2  and R 3  can combine to form an alkylene dioxy group. The invention is useful for rheumatic diseases.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates to novel flavone and isoflavonederivatives of use therapeutically and more particularly to novelflavone derivatives carrying an acid group, to their therapeuticapplication in the treatment of rheumatic diseases, and to a process fortheir preparation.

2. Description of the Related Art

A large number of variously substituted flavone derivatives have beendisclosed in the literature, as have their pharmacological properties ofuse in numerous therapeutic applications, such as, for example, thetreatment of asthma, of inflammatory diseases, of gastrointestinalconditions, of allergies or of certain cancerous tumors.

For example, U.S. Pat. No. 5,399,584 discloses flavone derivatives whichcan be used for protecting the wall of the gastrointestinal tract incomplementing a treatment by means of nonsteroidal anti-inflammatories.Patent EP 290 915 discloses flavone-3-carboxylic acids presented ashaving a pharmacological activity in which the formation of oxygenradicals in the cells is inhibited, making it possible to envisage theiruse as anti-inflammatory medicaments. Flavone-4′-carboxylic acidssubstituted in the 7 position by an amide or sulfonamide group, of usein the treatment of diabetic neuropathies, are disclosed in patent FR 2543 140. Patent EP 237 986 discloses other flavone derivativessubstituted on the phenyl ring by a carboxylic acid or ester group whichexhibit antitumor properties.

Some carboxyflavones capable of exhibiting a useful activity in thetreatment of asthma have been described by M. E. Zwangstra et al., J.Med. Chemistry, (1998) 41, 1428-1438. Other flavone derivatives, suchas, for example, flavone-6-carboxylic acids, in particular6-carboxy-2′-isopropoxyflavone, exhibiting anti-allergizing propertiesand a spasmolytic activity, are disclosed in U.S. Pat. No. 4,157,334.Patent FR 2 689 127 discloses di(t-butyl)-3′,5′-4′-hydroxyflavones [sic]capable of being used in the treatment of dyslipidemias, ofatherosclerosis and of ischemic cardiopathies. Centaureidin, or5,7,3′-trihydroxy-3,6,4′-trimethoxy-flavone, is a flavonoid isolatedfrom Tanacetum microphyllum, described by M. J. Abad et al., J. Nat.Prod., Vol. 56, No. 7, pp. 1164-1173 (1993), exhibitinganti-inflammatory properties comparable with that [sic] ofphenylbutazone, confirmed experimentally on the mouse. The sameanti-inflammatory activity has been confirmed with regard to themetabolism of arachidonic acid (release of prostaglandin E₂ andleukotriene C₄) and has been described in Planta Med., Vol. 64, pp.200-203 (1998). However, no inhibiting effect on the cytokines involvedin the inflammatory process of rheumatic diseases has been observed.

In the field of medicaments intended for the treatment of certainpathologies, such as arthrosis, rhein derivatives, in particulardiacerhein, have been described as being particularly effective at highdoses. However, one of the disadvantages related to the use of thesecompounds is that they can exhibit, in some subjects, troublesome sideeffects according to the dosage used and in particular a laxativeeffect. It is therefore desirable to be able to have availableanti-inflammatory medicaments having an at least equal therapeuticeffectiveness which are devoid of the side effects intrinsic to rheins.

SUMMARY OF THE INVENTION

A subject matter of the present invention is novel flavone derivatives,and more particularly flavone and isoflavone derivatives carrying anacid group in the 7 position, exhibiting advantageous anti-inflammatoryproperties which allow them to be used as medicaments in the treatmentof certain rheumatic diseases, such as arthrosis or rheumatoidarthritis.

Another subject matter of the invention is a process for the preparationof flavone and isoflavone derivatives carrying an acid group in the 7position starting from products which are readily accessible oravailable commercially.

Finally, a subject matter of the invention is the therapeuticapplication of the novel flavone and isoflavone derivatives carrying anacid group in the 7 position, more particularly in the treatment ofrheumatic diseases in human and veterinary therapy, and the use of saidflavone and isoflavone derivatives in the preparation of a medicamentfor the treatment of rheumatic diseases, such as arthrosis or rheumatoidarthritis.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

The novel flavone and isoflavone derivatives in accordance with thepresent invention can be represented by the general formulae (Ia) and(Ib) below:

in which X represents a group of formula —COOR or —PO(OR)₂, R representsa hydrogen atom or an alkali metal or alkaline earth metal atom, or alinear or branched lower alkyl group comprising 1 to 5 carbon atoms, R₁represents a hydroxyl group, a linear or branched lower alkoxy groupcomprising 1 to 5 carbon atoms or an acyloxy group comprising 1 to 5carbon atoms, R₂ and R₃, which are identical or different, represent ahydrogen or halogen atom or a trifluoromethyl group, a trichloromethylgroup, a hydroxyl group, a linear or branched alkoxy group comprising 1to 5 carbon atoms or an acyloxy group comprising 1 to 5 carbon atoms, orR₂ and R₃ can combine to form an alkylenedioxy group.

In the above formulae (Ia) and (Ib), X preferably represents acarboxylic or phosphoric acid group or an ester in which R is a methylor ethyl group, and R₁ preferably represents a hydroxyl, acetoxy ormethoxy group.

R₂ preferably represents a hydrogen, chlorine or fluorine atom, atrifluoromethyl group, a carboxyl group or an alkoxy group, and inparticular a methoxy group, and R₃ is preferably a hydrogen atom. Thesubstituent represented by R₂ is preferably situated in the 4′ positionof the phenyl ring. R₂ and R₃ can combine in order together to form anethylenedioxy or methylenedioxy group.

When the X substituent is [lacuna] carboxylic acid derivative, itpreferably represents the —COOH or —COOCH₃ group. When it is aphosphoric acid derivative, it preferably represents a —PO(OH)₂ or—PO(OCH₃)₂ group.

The derivatives of the invention can be provided in particular in theform of carboxylic acid salts having one or other of the above formulae(Ia) and (Ib) where X is a —COOR group, R being more particularly asodium atom or a potassium atom.

The novel flavone derivatives represented by the above formula (Ia) canbe prepared from the 5,7-dihydroxyflavones represented by the generalformula (IIa) below

in which the R₂ and R₃ substituents have the same meanings as in theformula (Ia), by reaction with a trifluoroalkanesulfonic anhydride inthe presence of a nonprotic base in an appropriate solvent, thenreaction with an acid chloride or an acid anhydride in the presence of anonprotic base, to form the derivatives of formula (IIIa) below

in which Z is a pivaloyl, methoxymethyl or trialkylsilyl group, then acarbonylation is carried out in the presence of a palladium-basedcatalyst, a phosphorus-comprising ligand and an alcohol, in anappropriate solvent, and the protective groups in the 5 and 7 position[sic] are removed.

Deprotection can be carried out in a known way, depending on theprotective groups used. For example, deprotection can be carried out ina basic medium for ester functional groups, in the presence of potassiumfluoride or tetrabutylammonium fluoride for a trimethylsilyl ester, orin an acidic medium for a methoxymethyl group.

Isoflavone derivatives of formula (Ib) are prepared analogously from thecorresponding 5,7-dihydroxy-isoflavones represented by the formula (IIb)below,

in which the R₂ and R₃ substituents have the same meanings as in theformula (Ib), in order to obtain the intermediate of formula (IIIb)

in which Z, R₂ and R₃ have the same meanings as above, and thentreatment via the same reaction scheme.

The reaction of the trifluoroalkanesulfonic anhydride with thedihydroxyflavone of formula (II) is carried out in the presence of anonprotic base which can advantageously be chosen from pyridine andtriethylamine and it is preferably carried out in a solvent, such asdichloromethane.

The trifluoroalkanesulfonic anhydride used in the process according tothe invention is preferably trifluoromethanesulfonic anhydride. Thechloride used in the reaction for the preparation of the derivatives offormula (IIIa) can be chosen from pivaloyl chloride, methoxymethylchloride or else a trialkylsilyl chloride, in the presence of anonprotic base, such as pyridine.

The palladium-based catalyst used in the carbonylation stage of theprocess according to the invention can, for example, be Pd(OAc)₂ in thepresence of carbon monoxide. The phosphorus-comprising derivative can,for example, be 1,3-bis(diphenylphosphino)propane and the alcohol can,for example, be methanol or 2-(trimethylsilyl)ethanol. The solvent usedin this stage is preferably DMF or DMSO.

It may be observed that the starting flavones represented by the generalformula (IIa) might be used for the preparation of3,5,7-trihydroxyflavones, the hydroxyl group of which in the 7 positionwould behave like the corresponding group in the 5,7-dihydroxyflavones,whereas the hydroxyl group of which in the 3 position would behave likethe group in the 5 position. These trihydroxyflavones can be preparedfrom the corresponding dihydroxyflavones comprising a hydrogen atom inthe 3 position by reaction with dimethyldioxirane in acetone, accordingto the method of W. Adam et al., J. Org. Chem., (1991) 56, 7292-7297, orby reaction with iodosylphenyl diacetate according to the method of R.M. Moriarty et al., J. Heterocycl. Chem., (1985) 22, 583. In contrast,in the isoflavone series, only the 5,7-dihydroxy derivatives are stable,unlike the highly unstable 2,5,7-trihydroxyflavones [sic].

The experiments carried out on the derivatives of the present inventionhave demonstrated advantageous pharmacological properties and inparticular a significant inhibiting effect on the production ofinflammatory cytokines involved in rheumatic disease. These results makeit possible to envisage their use in the treatment of arthrosis and ofrheumatoid arthritis, and very particularly of arthrosis.

Furthermore, the tests carried out have shown that the 7-carboxyflavoneand 7-carboxyisoflavone derivatives according to the present inventionare potentially more active than the reference anti-inflammatories, suchas rhein derivatives, in particular diacerhein (rhein being the activemetabolite of diacerhein), commonly used in human therapy in thetreatment of arthrosis. On the other hand, they do not exhibit thelaxative side effects inherent in these known medicaments. These resultsare doubtless due to the fact that the flavone derivatives do notpossess the quinone ring regarded as responsible for the laxativeeffect, but retain the inhibiting properties with respect to interleukin1 and other cytokines.

The inhibiting activity on the secretion of inflammatory cytokines ofthe compounds of the invention was tested in vitro, more particularly onthe secretion of IL-1 (interleukin 1) and on IL-6 and TNFα (tumornecrosis factor), which are the main cytokines related to the arthroticprocess.

The tests on these three cytokines were carried out on PBMC (PeripheralBlood Mononuclear Cells) cells according to the method of Schindler (R.Schindler et al., Blood, (1990) 75, 40-47) using cycloheximide (IL-1)and dexamethasone (IL-6, TNFα) as reference products.

The effect of the derivatives of the invention on the secretion ofprostaglandins (PGE₂), which increase articular inflammation, and ofleukotriene (LTB₄) was measured on differentiated HL-60 cells using themethods of Honda (M. Honda et al., Diabetes Res., (1990) 14, 43-46) andof Bennett (C. F. Bennett et al., Biochem. J., (1993) 289, 33-39),respectively, using indomethacin and nordihydroguaiaretic acid asreference products.

The study of the secretion of oxygen, making it possible to evaluate thestate of stress of the cell, was carried out on HL-60 cells according tothe method of Lorico (A. Lorico et al., Biochem. Pharmacol., (1986) 35,2443-2445).

Tests were also carried out on the stimulation of NO synthase, giventhat interleukin 1 increases the production of NO by stimulation of NOsynthase (NOS). These tests were carried out according to the method ofTayeh (M. A. Tayeh et al., J. Biol. Chem., (1989) 264, 19654-19658).

The results of the tests carried out with the flavone derivatives of theinvention described in examples 1, 4 and 6 above [sic] are combined inthe following table. The tests were carried out in duplicate, atconcentrations of 1 and 10 μM. The results are expressed as percentageof inhibition.

Results Example μM IL1β IL6 TNFα 1 10 96 98 32 1 15 50 61 4 1 <10 56 na6 10 72 100 na na: result not available (test not carried out).

These results show that the flavone derivatives according to the presentinvention exert significant inhibiting effects on IL-1 and IL-6. Thederivative of example 4 furthermore exhibits the distinctive feature ofstimulating the secretion of prostaglandins. The percentages ofinhibition are very high with respect to those observed with referenceantiarthrotic inflammatories, which are rhein and diacerhein.

The toxicological studies carried out have shown that the derivatives ofthe invention have a low toxicity at the doses normally used intreatments.

The pharmacological properties of the flavone and isoflavone derivativesaccording to the present invention, combined with their low toxicity,show that they can advantageously be used in the treatment of rheumaticdiseases and very particularly of arthrosis. They can be presented inthe form of esters or of salts, as a mixture, if appropriate, withpharmaceutically acceptable carriers or excipients.

The flavone derivatives in accordance with the present invention can beadministered in the forms usual in the pharmaceutical art, and forexample in the form of tablets, capsules, including gelatin capsules,injectable solutions, solutions to be taken orally, transdermal gels,and the like, suited to the administration route chosen, that is to saygenerally by the oral, parenteral or transdermal route. The workingdosage is adjusted according to the seriousness of the condition to betreated, the age and the weight of the patient, and the method ofadministration used. The single doses are generally between 10 mg and 5g per day, taken one to three times.

The following examples describe the preparation of derivatives inaccordance with the present invention, given without implied limitation.

EXAMPLE 1 5-Hydroxy-2-phenyl-4-oxo-4H-chromene-7-carboxylic acid

12.7 ml of pyridine and then 6.6 ml of trifluoromethanesulfonicanhydride are added to a solution of 200 ml of dichloromethanecomprising 10 g of 5,7-dihydroxyflavone while maintaining thetemperature at 0° C. After reacting for approximately 3 h at 0° C., thereaction mixture is neutralized with a 1N hydrochloric acid solution andthen extracted with dichloromethane.

After evaporation of the solvent, 13.9 g (92% yield) of7-trifluoromethanesulfonyloxy-5-hydroxy-2-phenyl-4-oxo-4H-chromene arerecovered in the form of a white powder, the chemical structure of whichis confirmed by chromatography and infrared spectrum, corroborated byNMR and mass spectrum.

Rf=0.58 (AcOEt/PE=30/70)

I.R. (cm⁻¹): 1655 (C═O), 1620 (C═C), 1436 (S═O).

0.16 ml of pivaloyl chloride is added to the product obtained asindicated above (330 mg) in solution in 4 ml of pyridine at 0° C. andreaction is allowed to take place for approximately 48 h whilemaintaining the temperature at 0° C.

After separating by flash chromatography (eluents AcOEt/EP=5/95 to10/90),7-trifluoromethane-sulfonyloxy-2-phenyl-5-pivaloyloxy-4-oxo-4H-chromene(95% yield) is obtained in the form of a white powder exhibiting amelting point M.p.=126-128° C.

Rf=0.65 (AcOEt/EP =10/90)

I.R. (cm⁻¹): 1752 (C═O ester), 1657 (C═O), 1614 (C═C), 1427 (S═O).

The above derivative (200 mg) is subsequently mixed with 8.7 mg of1,3-bis(diphenylphosphino)propane and 4.7 mg of Pd(OAc)₂ under anatmosphere of carbon monoxide in a three-necked round-bottomed flask andis treated [lacuna] 0.2 ml of 2-(trimethylsilyl)ethanol in the presenceof 0.12 ml of triethylamine and 0.9 ml of DMSO. The mixture is stirredat 70° C. for approximately 3 h, extracted with dichloromethane andwashed with a 1N hydrochloric acid solution.

After separating by flash chromatography (eluents AcOEt/PE=5/95 to10/90), 181 mg of 2-(trimethylsilyl)ethyl2-phenyl-5-pivaloyloxy-4-oxo-4H-chromene-7-carboxylate (91% yield) areobtained in the form of white crystals exhibiting a melting pointM.p.=205° C.

Rf=0.26 (CH₂Cl₂/MeOH=97/3).

202 mg of tetrabutylammonium fluoride, in solution in 2 ml oftetrahydrofuran, are added to the above carboxylate (180 mg) at 0° C.,reaction is then allowed to take place at ambient temperature forapproximately 19 h and a 1N sodium hydroxide solution (4.1 ml) is added.After 72 h, the mixture is hydrolyzed with a 1N hydrochloric acidsolution and then extracted with ethyl acetate.

The 5-hydroxy-2-phenyl-4-oxo-4H-chromene-7-carboxylic acid thusobtained, after purification by recrystallization from amethanol/chloroform (1-9) mixture, is provided in the form of a yellowpowder.

Melting point M.p.=270° C. (decomposition).

Rf=0.24 (CH₂Cl₂/MeOH=95/5).

I.R. (cm⁻¹): 1724 (COOH), 1656 (C═O), 1614 (C═C).

¹H NMR (CDCl₃/CD₃OD=9/1) δ ppm: 6.74 (s, 1H, H-3), 7.40 and 7.66 (2s,2H, H-6 and H-8), 7.48-7.51 (m, 3H, H-3′ and H-4′), 7.88 (d, 2H, J=6.4Hz, H-2′).

¹³C NMR (DMSO [sic]) δ ppm: 106.4, 108.9, 111.3 and 112.8 (C-3, C-8, C-6and C-4a), 127.1 (C-2′), 129.5 (C-3′), 130.6 (C-1′), 132.9 (C-4′), 137.6(C-7), 156.0, 160.1, 165.1 and 166.1 (C-5, C-2, C-8a and COOH), 183.3(C-4).

EXAMPLE 2 7-Dimethoxyphosphoryl-5-hydroxy-2-phenyl-4-oxo-4H-chromene

7-Trifluoromethanesulfonyloxy-2-phenyl-5-pivaloyloxy-4-oxo-4H-chromene(500 mg), a synthetic intermediate obtained in example 1, is treatedwith 0.12 ml of dimethyl phosphite in the presence of 0.24 ml ofdiisopropylethylamine and of 61 mg oftetrakis(triphenylphosphine)palladium in solution in 2.5 ml ofacetonitrile.

After heating at 70° C. for 7 h, the reaction mixture is neutralizedwith a 1N hydrochloric acid solution and then extracted withdichloromethane.

After separating by flash chromatography (eluents AcOEt/PE=5/95 to50/50), 383 mg of7-dimethoxy-phosphoryl-2-phenyl-5-pivaloyloxy-4-oxo-4H-chromene (84%yield) are obtained in the form of a white powder exhibiting a meltingpoint M.p.=165-167° C.

The above derivative is added to a solution of sodium hydroxide (5 ml),of water (10 ml) and of methanol (10 ml). After reacting at ambienttemperature for 23 h, the reaction mixture is acidified with a 1Nhydrochloric acid solution. The precipitate formed is washed with water.After recrystallizing from a methanol/chloroform mixture,7-dimethoxyphosphoryl-5-hydroxy-2-phenyl-4-oxo-4H-chromene is obtainedwith a yield of 90% in the form of a yellow precipitate.

Melting point M.p.=219° C.

Rf=0.25 (CH₂Cl₂/MeOH=70/30).

EXAMPLE 3 7-Dihydroxyphosphoryl-5-hydroxy-2-phenyl-4-oxo-4H-chromene

0.55 ml of bromotrimethylsilane is added to the product from example 2in solution in 13 ml of dichloromethane. After reacting at ambienttemperature for 21 h, the solvent is evaporated.

After recrystallizing from an ethanol/chloroform mixture,7-dihydroxyphosphoryl-5-hydroxy-2-phenyl-4-oxo-4H-chromene is obtainedin the form of a yellow powder with a yield of 68%.

Melting point M.p.=293-296° C. (decomposition).

I.R. (cm⁻¹): 1655 (C═O), 1616 (C═C), 1261 (P═O).

¹H NMR (DMSO [sic]) δ ppm: 6.98 and 7.44 (2s, 2H, J=13.5 Hz, H-6 andH-8), 7.16 (s, 1H, H-3), 7.59-7.65 (m, 3H, H-3′ and H-4′), 8.15 (d, 2H,J=6.9 Hz, H-2′), 12.63 (s, OH).

¹³C NMR (DMSO [sic]) δ ppm: 107.7 (C-3), 110.8 (C-4a), 111.3 and 113.9(J=9 Hz, C-6 and C-8), 128.4 (C-2′), 130.9 (C-3′), 132.1 (C-1′), 134.2(C-4′), 156.9 and 161.1 (J=20 Hz, C-5, C-2, C-8a), 166.3 (C-2), 183.2(C-4).

EXAMPLE 45-Hydroxy-0.2-(4′-methoxyphenyl)-4-oxo-4H-chromene-7-carboxylic acid

The preparation is carried out as shown in example 1 under the sameoperating conditions, the starting 5,7-dihydroxyflavone being replacedwith (4′-methoxyphenyl)-5,7-dihydroxyflavone [sic].

2-(Trimethylsilyl)ethyl2-(4′-methoxyphenyl)-5-pivaloyoxy-4-oxo-4H-chromene-7-carboxylate isthus obtained, which product is treated under the same conditions as inexample 1 to provide5-hydroxy-2-(4′-methyoxyphenyl)-4-oxo-4H-chromene-7-carboxylic acid.

Melting point M.p.=277-278° C.

Rf=0.53 (CH₂Cl₂/MeOH=90/10).

EXAMPLE 5 5-Hydroxy-3-(4′-methoxyphenyl)-4-oxo-4H-chromene-7-carboxylicacid

This derivative is obtained as in the preceding example, the startingflavone being replaced with the corresponding isoflavone.

5-Hydroxy-3-(4′-methoxyphenyl)-4-oxo-4H-chromene-7-carboxylic acid isthus obtained.

Rf=0.36 (CH₂Cl₂/MeOH=90/10)

I.R. (cm⁻¹): 1705 (COOH), 1653 (C═O), 1611 and 1583 (C═C).

¹H NMR (DMSO [sic]) δ ppm: 3?87 [sic] (s, 3H, CH₃O—), 7.09 (s, 1H, H-3),7.11 (d, 2H, H-6 and H-8), 8.113 (d, 2H, J=8.9 Hz, H-2′).

13C NMR (DMSO [sic]) δ ppm: 55.9 (CH₃), 104.6, 108.7 and 111.1 (C-3, C-6and C-8), 112.5 (C-4a), 114.9 (C-3′), 122.6 (C-1′), 129.1 (C-2 ), 137.5(C-7), 155.8, 160.0, 163.0, 165.2 and 166.1 (C-2, C-4′, C-5, C-8a andCOOH), 183.0 (C-4).

EXAMPLE 65-Hydroxy-2-(4′-trifluoromethylphenyl)-4-oxo-4H-chromene-7-carboxylicacid

The preparation is carried out as in example 1 under the same operatingconditions, the starting 5,7-dihydroxy-flavone being replaced with(4′-trifluoromethylphenyl)-5,7-di-hydroxyflavone [sic].

5-Hydroxy-3-(4′-trifluoromethylphenyl)-4-oxo-4H-chromene-7-carboxylicacid is thus obtained.

Melting point M.p.=278° C. (decomposition)

Rf=0.18 (CH₂Cl₂/MeOH=90/10).

¹H NMR (CDCl₃/CD₃OD=9/1) δ ppm: 6.88 (s, 1H, H-3), 7.49 and 7.74 (2d,2H, J=1.2 Hz, H-6 and H-8), 7.82 (d, 2H, J=8.3 Hz, H-3′), 8.09 (d, 2H,J=8.2 Hz, H-2′).

¹³C NMR (DMSO [sic]) δ ppm: 108.5, 109.6, 112.1 and 113.4 (C-3, C-4a,C-6 and C-8), 124.7 (q, J=271.0 Hz, CF₃), 126.97 (q, J=3.6 Hz, C-3′),128.6 (C-2′), 132.8 (q, J=32.0 Hz, C-4′), 135.2 (C-7), 138.8 (C-1),156.6, 160.7, 163.9 and 166.8 (C-2, C-5, C-8a and COOH), 184.0 (C-4).

1. Flavone and isoflavone derivatives represented by the followinggeneral formulae (Ia) and (Ib):

in which X represents a group of formula —COOR or —PO(OR)₂; R representsa hydrogen atom, an alkali metal or alkaline earth metal atom, or alinear or branched lower alkyl group having 1 to 5 carbon atoms; R₁represents a hydroxyl group, a linear or branched lower alkoxy grouphaving 1 to 5 carbon atoms or an acyloxy group having 1 to 5 carbonatoms; R₂ and R₃, which are identical or different, represent a hydrogenatom, a halogen atom, a trifluoromethyl group, a trichloromethyl group,a hydroxyl group, a linear or branched alkoxy group having 1 to 5 carbonatoms or an acyloxy group having 1 to 5 carbon atoms, or R₂ and R₃together with the carbon atoms to which they are attached combine toform an alkylenedioxy group.
 2. Derivatives according to claim 1,wherein X represents a carboxylic or phosphoric acid group or an esterin which R is a methyl group, and R₁ represents hydroxyl, acetoxy ormethoxy group.
 3. Derivatives according to claim 1, wherein R₂represents a hydrogen atom, a fluorine atom, a trifluoromethyl group, acarboxyl group or an alkoxy group and R₃ is a hydrogen atom, or R₂ andR₃ together form an ethylenedioxy or methylenedioxy group. 4.Derivatives according to claim 2, wherein X is a —COOH group, R₁ is ahydroxyl group and R₂ represents a hydrogen atom, a trifluoromethylgroup or a methoxy group situated in the 4′ position of the phenyl ring.5. Derivatives according to claim 1, wherein X is a —COOR group where Ris a sodium atom or a potassium atom.
 6. Derivatives according to claim1, wherein the derivatives are selected from the group consisting of5-hydroxy-2-phenyl-4-oxo-4H-chromene-7-carboxylic acid,7-dihydroxyphosphoryl-5-hydroxy-2-phenyl-4-oxo-4H-chromene,5-hydroxy-2-(4′-methoxyphenyl)-4-oxo-4H-chromene-7-carboxylic acid and5-hydroxy-2-(4′-trifluoromethylphenyl)-4-oxo-4H-chromene-7-carboxylicacid.
 7. Process for the preparation of flavone and isoflavonederivatives represented by the general formulae (Ia) and (Ib) accordingto claim 1, wherein a 5,7-dihydroxyflavone, represented by the followinggeneral formula (IIa) or (IIb)

in which R₂ and R₃, which are identical or different, represent ahydrogen atom, a halogen atom, a trifluoromethyl group, atrichloromethyl group, a hydroxyl group, a linear or branched alkoxygroup of 1 to 5 carbon atoms or an acyloxy group of 1 to 5 carbon atoms,or R₂ and R₃ together with the carbon atoms to which they are attachedcombine to form an alkylenedioxy group, is reacted with atrifluoroalkanesulfonic anhydride in the presence of a nonprotic base inan appropriate solvent, then an acid chloride or an acid anhydride isreacted in the presence of a nonprotic base, to form the derivatives offormula (IIIa) or (IIIb) below

in which Z is a pivaloyl, methoxymethyl or trialkylsilyl group, then acarbonylation is carried out in the presence of a palladium-basedcatalyst, a phosphorus-comprising ligand and an alcohol, in appropriatesolvent, and the protective groups in the 5 and 7 position are removedto provide the flavone and isoflavone derivatives of general formulae(Ia) and (Ib) according to claim
 1. 8. Process according to claim 7,wherein chloride is pivaloyl chloride, methoxymethyl chloride or atrialkylsilyl chloride.
 9. Process according to claim 7, wherein thenonprotic base is pyridine or triethylamine.
 10. Process according toclaim 7, wherein the carbonylation is carried out in the presence of apalladium-based catalyst composed of Pd(OAc)₂ in the presence of carbonmonoxide, the phosphorus-comprising ligand is1,3-bis(diphenyl-phosphino)propane and the alcohol is methanol or2-(trimethylsilyl)ethanol.
 11. Process according to claim 10, whereincarbonylation reaction is carried out in a solvent selected from thegroup consisting of DMF and DMSO.
 12. Pharmaceutical composition for usein human and veterinary therapy comprising a flavone or isoflavonederivative according to claim 1 and one or more pharmaceuticallyacceptable excipients or carriers.
 13. A method for treatment ofrheumatic diseases in a subject in need thereof comprising administeringto the subject a therapeutically effective amount of a flavone orisoflavone derivative according to claim
 1. 14. Derivatives according toclaim 2, wherein R₂ represents a hydrogen atom, a fluorine atom, atrifluoromethyl group, a carboxyl group or an alkoxy group and R₃ is ahydrogen atom, or R₂ and R₃ together form an ethylenedioxy ormethylenedioxy group.
 15. Derivatives according to claim 3, wherein X isa —COOH group, R₁ is a hydroxyl group and R₂ represents a hydrogen atom,a trifluoromethyl group or a methoxy group situated in the 4′ positionof the phenyl ring.
 16. Process according to claim 8, wherein thenonprotic base is chosen from pyridine and triethylamine. 17.Pharmaceutical composition for use in human and veterinary therapycomprising a flavone or isoflavone derivative according to claim 2 andone or more pharmaceutically acceptable excipients or carriers. 18.Pharmaceutical composition for use in human and veterinary therapycomprising a flavone or isoflavone derivative according to claim 3 andone or more pharmaceutically acceptable excipients or carriers. 19.Derivatives according to claim 1, wherein R₃ is a hydrogen atom and R₂is a hydrogen atom, a halogen atom, a trifluoromethyl group, atrichloromethyl group, a hydroxyl group, a linear or branched alkoxygroup having 1 to 5 carbon atoms or an acyloxy group having 1 to 5carbon atoms, wherein R₂ is situated in the 4′ position of the phenylring.